Cartilage covers all articulating surfaces and does, due to its unique structure, endow a joint with nearly frictionless motion. The coefficient of friction, defined as .mu.=frictional force (F)/applied load (W), for articular cartilage in a diarthrodial joint is 0.005-0.02 (human knee). As a comparison, the coefficient of friction for ice on ice is around five times higher (0.01-0.1), Mow, V. C., A. Ratcliffe and A. R. Poole "CARTILAGE AND DIARTHRODIAL JOINTS AS PARADIGMS FOR HIERARCHICAL MATERIALS AND STRUCTURES" Biomaterials, 13(2): 67-97 (1992).
The matrix of articular cartilage consists of 60-80% water (and dissolved ions and gases) by wet weight of articular cartilage and 20-40% structural molecules like collagen, proteoglycans, glycosaminoglycans and glycoproteins. Chondrocytes, the specialized cells in articular cartilage, are embedded in this matrix and occupy only about 10% of the volume and articular cartilage contains neither nerves nor lymphatic vessels nor blood vessels, Buckwalter, J. A., L. C. Rosenberg and E. B. Hunziker, "ARTICULAR CARTILAGE: COMPOSITION, STRUCTURE, RESPONSE TO INJURY, AND METHODS OF FACILITATING REPAIR", reprinted in ARTICULAR CARTILAGE AND KNEE JOINT FUNCTION: BASIC SCIENCE AND ARTHROSCOPY New York, Raven Press (1990) and Hunziker, E. B. "STRUKTURMOLEKULE DES KNORPELGEWEBES, DER SEHNEN UND BANDER", Kniegelenk und Kreuzbander, Berlin, Springer (1990) .
Two types of articular lesions can be differentiated. First, the chondral or superficial defect; this does not extend to or damage the subchondral bone. The subchondral bone is innervated, contains blood vessels, and connects the articular cartilage to the bone and bone marrow. Superficial cartilage lesions, not extending to the subchondral bone (i. e. partial thickness defects), may appear as a linear-crack type, a stellate fracture, a flap type, a fibrillation type, Bauer, M. and R. W. Jackson "CHONDRAL LESIONS OF THE FEMORAL CONDYLES: A SYSTEM OF ARTHROSCOPIC CLASSIFICATION" Arthroscopy, 4(2):97-102 (1988). Cartilage lesions are often of traumatic origin but do also occur without any obvious cause. Because of the lack of nerve supply, they usually do not cause pain. If symptoms occur, they are detected as delayed swelling of the synovium (the inner side of the joint capsule), with a intermittent locking as a result of a chondral fragment, or as recurrent effusions and crepitus, Scott, W. N. and J. N. Insall "INJURIES OF THE KNEE", reprinted in ROCKWOOD AND GREEN'S FRACTURES IN ADULTS, Philadelphia, J. B. Lippincott Company (1991). Such defects are notorious as they do not heal, do not show propensity for repair reactions, and show many similarities to the early stages of degenerative joint diseases, such as osteoarthritis. Secondly, the full-thickness defect; this extends to the subchondral bone, which contains nerves and blood vessels. It results for example from heavy trauma as a crater--or degrading type (Bauer et al, supra), or occurs in late stages of degenerative joint diseases, such as osteoarthritis. A symptom is often severe pain. Bleedings and repair reactions may occur, resulting in a vascularized fibrous type of cartilage which is however not sufficient to support joint function. Such repair tissue very rarely persists (Buckwalter et al, supra).
Currently, still various attempts are made to facilitate cartilage repair in chondral and subchondral defects. One approach is to drill through chondral defects into the subchondral bone which induces bleeding, Pridie, K. H. "A METHOD OF RESURFACING OSTEOARTHRITIC KNEE JOINTS" J Bone Joint Surg (Br) 41-B: 618-619 (1959). Through the bleeding repair reactions are induced and fibrocartilage is formed, but this tissue shows insufficient biomechanical properties and lacks long term persistence, Mitchell, N. and N. Shepard "THE RESURFACING OF ADULT RABBIT ARTICULAR CARTILAGE BY MULTIPLE PERFORATIONS THROUGH THE SUBCHONDRAL BONE" J Bone and Joint Surg 58-A: 230-233 (1976). Resurfacing of articular cartilage defects with periosteal and perichondrial grafts has been evaluated, Coutts, R. D., S. L. Y. Woo, D. Amiel, H. P. Von Schroeder and M. K. Kwan "RIB PERIOCHONDRIAL AUTOGRAFTS IN FULL-THICKNESS ARTICULAR CARTILAGE DEFECTS IN RABBITS" Clin Orthop 263-273 (1992); Homminga, G. N., S. K. Bulstra, P. S. M. Bouwmeester and A. J. Van Der Linden "PERICHONDRAL GRAFTING FOR CARTILAGE LESIONS OF THE KNEE" J Bone Joint Surg (Br) 72-B(6): 1003-7 (1990); Homminga, G. N., T. J. van der Linden, E. A. W. Terwindt-Rouwenhorst and J. Drukker, "REPAIR OF ARTICULAR DEFECTS BY PERICHONDRIAL GRAFTS: EXPERIMENTS IN THE RABBIT" Acta Orthop Scand 60(3): 326-329 (1989) and O'Driscoll, S. W., F. W. Keeley and R. B. Salter "DURABILITY OF REGENERATED ARTICULAR CARTILAGE PRODUCED BY FREE AUTOGENOUS PERIOSTEAL GRAFTS IN MAJOR FULL-THICKNESS DEFECTS IN JOINT SURFACES UNDER THE INFLUENCE OF CONTINUOUS PASSIVE MOTION" J Bone and Joint Surg 70-A(4): 595-606 (1988). Perichondrium and periosteum are thin connective tissue layers which cover fibrocartilage or bone, respectively. Most investigators suture the perichondrium or periosteum into a subchondral defect, thereby creating additional cartilage damage. Others obtained good results by gluing perichondrium onto chondral defects of rabbits knee joints using a commercial fibrin sealant (Tissucol), Homminga, G. N., T. J. van der Linden, E. A. W. Terwindt-Rouwenhorst and J. Drukker, "REPAIR OF ARTICULAR DEFECTS BY PERICHONDRIAL GRAFTS" Acta Orthop Scand 60(3): 326-329 (1989), an approach that did, however, require a two week immobilization of the joint. Joint immobilization has also been recommended when using fibrin sealant for the fixation of chondral or osteochondral fragments because of the poor resistance of the sealant to shear forces, Claes, L., C. Burri, G. Helbing and E. Lehner "BIOMECHANISCHE UNTERSUCHUNGEN ZUR FESTIGKEIT VERSCHIEDENER KNORPELKLEBUNGEN" Helv Chir Acta 48: 11-13 (1981). A major argument against the use of fibrin sealant is the possible transmission of human pathogenic viruses, e.g., human immune deficiency virus (HIV) and hepatitis B virus. For this reason, fibrin sealants composed of crude fractions of human blood plasma proteins are not permitted for use in the United States.
Removal of fibrillated or irregular cartilage (shaving off) has been evaluated as a therapeutic approach, but it has been shown that shaved articular cartilage of the human knee joint will not regenerate and may even cause an increase of fibrillation and cell necrosis, Schmid, A. and F. Schmid "RESULTS AFTER CARTILAGE SHAVING STUDIED BY ELECTRON MICROSCOPY" Am J Sports Med 15(4): 386-387 (1987). Shaving of the patellar cartilage in rabbits does not lead to significant repair, Mitchell, N. and N. Shepard "EFFECT OF PATELLAR SHAVING IN THE RABBIT" J Orthop Res 5: 388-392 (1987).
The use of cultured fetal chondrocytes embedded in a biomatrix containing fibrinogen, thrombin and additional components, Itay, S., A. Abramovici and Z. Nevo "USE OF CULTURED EMBRYONAL CHICK EPIPHYSEAL CHONDROCYTES AS GRAFTS FOR DEFECTS IN CHICK ARTICULAR CARTILAGE" Clin Orthop 220:284-303 (1987), or of bone-marrow-derived mesenchymal stem cells, Pineda, S. J., T. Goto, V. M. Goldberg and A. I. Caplan "OSTEOCHONDRAL PROGENITOR CELLS ENHANCE REPAIR OF LARGE DEFECTS IN RABBIT ARTICULAR CARTILAGE" Trans Orthop Res Soc 17 (2):598 (1992) as grafts, has been successful in chickens and induced full-thickness repair. It is not known whether successful transplantation of chondrocytes into superficial defects has occured in mammals or humans. The mechanical fixation (i. e. local immobilization) of transplants remains a problem in this approach.
Current treatment of cartilage fractures is often hampered by the failure of the tissue to adhere spontaneously. Stabilization of fragments with screws or Kirschner wires requires repeated surgical intervention, which results in additional trauma and destruction, and in spite of this, stable fixation is frequently not achieved. Cartilage fractures have to be reduced very precisely (best geometrical fit), otherwise fractures will heal through the formation of a fibrocartilage with insufficient biomechanical properties, Mitchell, N. and N. Shepard "HEALING OF ARTICULAR CARTILAGE IN INTRA-ARTICULAR FRACTURES IN RABBITS" J Bone and Joint Surg 62-A: 628-634 (1980).
Osteochondritis dissecans is an osteochondral lesion with an unknown, probably multifactorial etiology. Most patients with a loose osteochondral fragment in the joint have to undergo surgery, as nonoperative treatment has been shown to accelerate degenerative arthritis, Federico, D. J., J. K. Lynch and P. Jokl "OSTEOCHONDRITIS DISSECANS OF THE KNEE: A HISTORICAL REVIEW OF ETIOLOGY AND TREATMENT" Arthroscopy 6(3): 190-197 (1990). The options for fixation of osteochondral fragments include the use of compression-screws, Kirschnet wires, or a compression pinning system (hooked wires, anchoring screws, and bolts), Jakob, R. P. "THE TREATMENT OF OSTEOCHONDRITIS DISSECANS OF THE KNEE JOINT USING A NEW COMPRESSION WIRE SYSTEM" Z Unfallchir Versicherungsmed. 83(2): 104-110 (1990); Scott, D. J. and C. A. Stevenson "OSTEOCHONDRITIS DISSECANS OF THE KNEE IN ADULTS" Clin Orthop 76:82-86 (1990) and Smilie, I. "OSTEOCHONDRITIS DISSECANS", London, Livingston (1960). In most cases, a second operation is required in order to remove the metal. The usefulness of biological sealants in treatment of osteochondritis dissecans has not been evaluated so far.
The human meniscus is a discoid or semilunar slice of cartilage (consisting mainly of circumferentially orientated collagen fibers). It is present between joint surfaces, improves joint congruency and lessens point contact, as e.g. in the knee joint (Scott, W. N. and J. N. Insall, "INJURIES 0F THE KNEE", reprinted in ROCKWOOD AND GREEN'S FRACTURES IN ADULTS, Philadelphia, J. B. Lippincott Company (1991). The central and inner part of the meniscus consists of an avascular, aneural and alymphatic fibrocartilage, Arnoczky, S. P. and R. F. Warren "MICROVASCULATURE OF THE HUMAN MENISCUS" Am J Sports Med 10(2): 90-95 (1982). Only meniscal tears that occur in the vascular periphery, and that are 3 cm in length or shorter, respond to mechanical suturing. In other types of meniscal tears, the inner meniscal portions are generally excised, a treatment that does in most cases lead to degenerative joint disease, (Scott, W. N. and J. N. Insall "INJURIES OF THE KNEE", reprinted in ROCKWOOD AND GREEN'S FRACTURES IN ADULTS Philadelphia, J. B. Lippincott Company (1991)). A method for repairing all types of meniscal tears by use of an effective biological sealant would be of great clinical value. This would minimize, or even prevent, the high frequency of postoperative degenerative joint disease.
A number of substances are known to have the potential of stimulating chondrogenesis. For example, a collagen sponge implant can facilitate chondral repair, Speer, D. P., M. Chvapil, R. G. Volz and M.D. Holmes "ENHANCEMENT OF HEALING IN OSTEOCHONDRAL DEFECTS BY COLLAGEN SPONGE IMPLANTS." Clin Orthop 144: 326-335 (1979). A number of proteins can promote chondrogenesis, like transforming growth factor beta, Seyedin, S. M., A. Y. Thompson and H. Bentz "CARTILAGE-INDUCING FACTOR-.alpha.: APPARENT IDENTITY TO TRANSFORMING GROWTH FACTOR-.beta." J Biol Chem. 261(13): 5693-5695 (1986) and Sporn, M. B., A. B. Roberts and L. M. Wakefieland R. K. Assoiand "TRANSFORMING GROWTH FACTOR-.beta.: BIOLOGICAL FUNCTION AND CHEMICAL STRUCTURE" Science 233: 532-534 (1986), fibroblast growth factor, Zapf, J. and E. R. Froesch "INSULIN-LIKE GROWTH FACTORS/SOMATOMEDINS: STRUCTURE, SECRETION, BIOLOGICAL ACTIONS AND PHYSIOLOGICAL ROLE" Horm Res 24: 121-130 (1986) and insulin-like growth factor, Hauschka, P. V., A. E. Mavrakos and M. D. Iafrati "GROWTH FACTORS IN BONE MATRIX: ISOLATION OF MULTIPLE TYPES BY AFFINITY CHROMATOGRAPHY ON HEPARIN-SEPHAROSE" J Biol Chem 261(27): 12665-12674 (1986). Further work is required to identify the most useful factors and to find ways to deliver and anchor them into the site of injury (Buckwalter et al, supra). An improved biological sealant could, however, greatly facilitate the clinical usefulness of such bioactive agents.
An effective biological sealant which may be used without risk of virus transmission, leading to hepatitis B or acquired immune deficiency syndrome (AIDS), would indeed open new therapeutic possibilities in all the situations described above.